Preparation Method for Glufosinate

ABSTRACT

A preparation method for glufosinate or a salt, an enantiomer or a mixture of enantiomers in all ratios thereof, the method being especially suitable for the preparation of glufosinate, and greatly shortening steps in an existing preparation process. Especially in the preparation of L-glufosinate, the product can effectively retain the ee value of the raw materials.

FIELD OF THE INVENTION

The present invention relates to a preparation method for glufosinate.

BACKGROUND OF THE INVENTION

Glufosinate is an important herbicide.

SUMMARY OF THE INVENTION

The present invention provides a method for preparing glufosinate offormula (I) or a salt, an enantiomer thereof or a mixture of theenantiomers in all ratios, comprising the following steps:

-   a) reacting a compound of formula (II) or a salt, an enantiomer    thereof or a mixture of the enantiomers in all ratios,

-   

-   with one or more compounds of formula (III) or a mixture;    -   the above mixture being a mixture comprising one or more        compounds of formula (IV) and one or more compounds of formula        (V); or a mixture comprising one or more compounds of        formula (IV) and one or more compounds of formula (III); or a        mixture comprising one or more compounds of formula (V) and one        or more compounds of formula (III); or a mixture comprising one        or more compounds of formula (III), one or more compounds of        formula (IV) and one or more compounds of formula (V);

    -   

    -   

    -   

-   b) reacting the intermediate, no matter whether it is isolated or    not, in the presence of water and an acid or a base to obtain the    glufosinate (I) or a salt, an enantiomer thereof or a mixture of the    enantiomers in all ratios;    -   wherein when PG is an amino protecting group, a step of removing        the amino protecting group can be further comprised;

    -   wherein: LG is Hal¹, -OTs or Hal

    -   

    -   Hal¹ and Hal² are each independently halogen, e.g., fluorine,        chlorine, bromine or iodine;

    -   PG is hydrogen or an amino protecting group, and the amino        protecting group preferably is -C(=O), -C(=O)OR or -S(=O)₂R;

    -   A is -NHR₁, -NR₁R_(1′) or -OR1;

    -   R, R₁, R_(1′), R₂, R₃ and R₄ are each independently selected        from the group consisting of C₁-C₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, C₆₋₁₂ aralkyl, 5- to 14-membered heteroaryl and 3-        to 10-membered heterocyclyl, and when the mixture comprises the        mixture of one or more compounds of formula (IV) and one or more        compounds of formula (III), or when the mixture comprises the        mixture of one or more compounds of formula (III), one or more        compounds of formula (IV) and one or more compounds of formula        (V), R₂ is either R₃ or R₄;

    -   the chiral carbon atom is labeled with *; and

    -   provided that at least one of the following conditions is met:        -   1) the compound of formula (II) is not

        -   

        -   2) the compound of formula (III) is not

        -   

        -   3) the compound of formula (IV) is not

        -   

        -   4) the compound of formula (V) is not

        -   

The present invention further provides a method for preparingenantiomerically pure glufosinate of formula (I) or a salt thereof,

the method comprises the following steps:

-   a1) reacting an enantiomerically pure compound of formula (II) or a    salt thereof,

-   

-   with a compound of formula (III),

-   

-   or one or more compounds of formula (III) or a mixture;    -   the above mixture being a mixture comprising one or more        compounds of formula (IV) and one or more compounds of formula        (V); or a mixture comprising one or more compounds of        formula (IV) and one or more compounds of formula (III); or a        mixture comprising one or more compounds of formula (V) and one        or more compounds of formula (III); or a mixture comprising one        or more compounds of formula (III), one or more compounds of        formula (IV) and one or more compounds of formula (V);

    -   

    -   

    -   

-   b1) reacting the intermediate, no matter whether it is isolated or    not, in the presence of water and an acid or a base to obtain the    enantiomerically pure glufosinate (I) or a salt thereof;    -   wherein when PG is an amino protecting group, a step of removing        the amino protecting group can be further comprised; wherein        -   LG is Hal¹, -OTs or Hal¹⁻

        -   

        -   Hal¹ and Hal² are each independently halogen, e.g.,            fluorine, chlorine, bromine or iodine;

        -   PG is hydrogen or an amino protecting group, and the amino            protecting group preferably is -C(=O)R, -C(=O)OR or            -S(=O)₂R;

        -   A is -NHR₁, -NR₁R₁ or -OR₁;

        -   R, R₁, R_(1′), R₂, R₃ and R₄ are each independently selected            from the group consisting of C₁-C₆ alkyl, C₃₋₁₀ cycloalkyl,            C₆₋₁₀ aryl, C₆₋₁₂ aralkyl, 5- to 14-membered heteroaryl and            3- to 10-membered heterocyclyl, and when the mixture            comprises the mixture of one or more compounds of            formula (IV) and one or more compounds of formula (III), or            when the mixture comprises the mixture of one or more            compounds of formula (III), one or more compounds of            formula (IV) and one or more compounds of formula (V), R₂ is            either R₃ or R₄;

        -   the chiral carbon atom is labeled with *;

        -   provided that at least one of the following conditions is            met:            -   1) the compound of formula (II) is not

            -   

            -   2) the compound of formula (III) is not

            -   

            -   3) the compound of formula (IV) is not

            -   

            -   4) the compound of formula (V) is not

        -   

In certain specific embodiments, one compound of formula (III) isemployed.

In certain specific embodiments, a mixture of one compound of formula(IV) and one compound of formula (V) is employed, and the mixture can befurther added with a compound of formula (III) in any ratio.

Further, the enantiomeric ratio is (L):(D)-enantiomer or(D):(L)-enantiomer of 50.5:49.5 to 99.5:0.5.

Further, the enantiomeric ratio is (L):(D)-enantiomer of 50.5:49.5 to99.5:0.5.

In some embodiments, R is C₁-C₆ alkyl or C₆₋₁₀ aryl, preferably ismethyl, ethyl, tert-butyl, phenyl or p-methylphenyl.

In some embodiments, said PG is hydrogen, -C(=O)CH₃, -C(=O)Ph,-C(=O)OC₂H₅, -C(=O)OC(CH₃)₃ or

In some embodiments, said Hal¹ is chlorine, bromine or iodine.

In some embodiments, LG is chlorine, bromine, iodine, -OTs or

In some embodiments, said Hal² is chlorine.

In some embodiments, said R₁, R_(1′), R₂, R₃ and R₄ are eachindependently C₁-C₆ alkyl or C₆₋₁₂ aralkyl, preferably are C₁-C₄ alkylor benzyl.

In some embodiments, said R₁ and R_(1′) are each independently methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl or benzyl.

In some embodiments, A is -NHCH₂CH₂CH₂CH₃, -N(CH₃)₂, -OCH₃, -OCH₂CH₃,-OCH₂CH₂CH₃, -OCH(CH₃)₂, -OCH₂CH₂CH₂CH₃, -OCH₂CH(CH₃)₂ or -OBn.

In some embodiments, said R₂ is methyl, ethyl, n-propyl, isopropyl,n-butyl or isobutyl, preferably is n-propyl, isopropyl or n-butyl.

In some embodiments, said R₃ is methyl, ethyl, n-propyl, isopropyl,n-butyl or isobutyl, preferably is n-propyl, isopropyl or n-butyl.

In some embodiments, said R₄ is methyl, ethyl, n-propyl, isopropyl,n-butyl or isobutyl, preferably is n-propyl, isopropyl or n-butyl.

In certain specific embodiments, the mixture is a mixture of one or morecompounds of formula (IV) and one or more compounds of formula (III),and the molar ratio of the compounds of formula (IV) to the compounds offormula (III) is (0.9-1.1):1 or (0.05-1.1):1; or the mixture is amixture of one or more compounds of formula (V) and one or morecompounds of formula (III), and the molar ratio of the compounds offormula (V) to the compounds of formula (III) is (0.9-1.1):1 or(0.05-1.1):1; or the mixture is a mixture comprising one or morecompounds of formula (IV) and one or more compounds of formula (V), andthe molar ratio of the compounds of formula (IV) to the compounds offormula (V) is (0.9-1.1):1.

Further, in aforementioned step a) or a1), the reaction can proceed atroom temperature, the reaction temperature can be 20-200° C., andpreferably 90-140° C. in consideration of reaction efficiency.

Further, the aforementioned step a) or a1) is carried out in thepresence of a base.

Further, the base in aforementioned step a) or a1) is an organic base orammonia.

Further, in aforementioned step a) or a1), the organic base is selectedfrom the group consisting of an organic amine, pyridine or a pyridinederivative having 1-3 substituents attached to one or more carbon atomsin the heterocycle, piperidine or a piperidine derivative having 1-3substituents attached to one or more carbon atoms in the heterocycle.

Further, the organic base is selected from the group consisting oftriethylamine, piperidine or pyridine.

Further, in aforementioned step a) or a1), the molar ratio of the baseto the total amounts of the compound of formula (III) and the compoundof formula (V) is (1-10):1.

Further, in aforementioned step a) or a1), the reaction is carried outunder a solvent-free condition or in an inert solvent.

Further, in aforementioned step a) or a1), the inert solvent is selectedfrom any one or more of benzene solvents, amide solvents, hydrocarbonsolvents, halogenated hydrocarbon solvents, sulfone or sulfoxidesolvents, ether solvents or ester solvents; preferably, the inertsolvent is selected from any one or more of benzene solvents, amidesolvents, halogenated hydrocarbon solvents, ether solvents or estersolvents.

Further, in aforementioned step a) or a1), the inert solvent is selectedfrom any one or more of chlorobenzene, trimethylbenzene, 1,4-dioxane,1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone,N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran,methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butylacetate.

Further, in aforementioned step a) or a1), the molar ratio of thecompound of formula (III) or the mixture to the compound of formula (II)is 1:(0.8-10), preferably 1:(1-3); or the molar ratio of the compound offormula (II) to the compound of formula (III) or the mixture is1:(0.8-10), preferably 1:(1-3).

Further, the total reaction time of aforementioned step a) or a1) is 0.5hour to 25 hours, preferably 1 hour to 20 hours or 1 hour to 15 hours,most preferably 1 hour to 5 hours.

Further, in aforementioned step b) or b 1), an inorganic acid or anorganic acid is added.

Further, the inorganic acid is hydrochloric acid or sulfuric acid.

Further, in aforementioned step b) or b1), the base is an inorganic baseor an organic base.

Further, the base is alkali metal hydroxide, alkali-earth metalhydroxide, alkali metal carbonate, alkali-earth metal carbonate, alkalimetal bicarbonate or alkali-earth metal bicarbonate.

Further, the base is NaOH, KOH or Ba(OH)₂.

Further, in aforementioned step b) or b1), the reaction temperature is20-150° C.

In some embodiments, the present disclosure provides a compound offormula (II) or a salt thereof,

wherein the compound of formula (II) is selected from the groupconsisting of:

In some embodiments, the present disclosure provides use of theaforementioned compound in the preparation of glufosinate or a saltthereof, or L-glufosinate or a salt thereof.

The method of the present invention is particularly suitable for thepreparation of glufosinate, and substantially reduces the steps of theexisting preparation processes. In particular, in the preparation ofL-glufosinate, the product can effectively maintain the ee value of theraw material. For example, when an enantiomerically pure raw material(e.g., the enantiomeric excess percentage (% ee) is greater than 90%) isemployed, the enantiomeric excess percentage (% ee) of the preparedL-glufosinate is greater than e.g., 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90% or 95%.

Unless otherwise specified, the terms used in the specification andclaims have the following meanings.

The term “amino protecting group” refers to a group that can be attachedto a nitrogen atom in an amino group to protect the amino group fromparticipating the reaction and can be easily removed in the subsequentreactions. Suitable amino protecting groups include, but are not limitedto, the following protecting groups:

carbamate group of formula -C(=O)O-R^(a), wherein R^(a) is e.g., methyl,ethyl, tert-butyl, benzyl, phenethyl, CH₂=CH-CH₂-, etc.; amide group offormula -C(=O)-R^(b), wherein R^(b) is methyl, ethyl, phenyl,trifluoromethyl, etc.; N-sulfonyl derivative group of formula-S(=O)₂-R^(c), wherein R^(c) is e.g., tolyl, phenyl, trifluoromethyl,2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene,etc.

The term “alkyl” refers to a saturated aliphatic hydrocarbon group,including linear and branched groups having 1 to 18 carbon atoms. Alkylhaving 1 to 6 carbon atoms (i.e., C₁-C₆ alkyl), such as methyl, ethyl,propyl, 2-propyl, n-butyl, isobutyl, tert-butyl and pentyl, ispreferred. The alkyl can be substituted or unsubstituted, and whensubstituted, the substituent can be halogen, nitro, sulfonyl, ether oxy,ether thio, ester, thioester or cyano.

The C₁-C₄ alkyl is linear or branched, comprising saturated hydrocarbonchain having 1 to 4 carbon atoms. It can be methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

As used herein, the term “cycloalkyl” refers to a saturated monocyclicor polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, suchas cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridgedcyclic system (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl,bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthalene,etc.)), which is optionally substituted with one or more (e.g., 1 to 3)suitable substituents. The cycloalkyl has 3 to 15 carbon atoms. Forexample, the term “C₃₋₁₀ cycloalkyl” refers to a saturated monocyclic orpolycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 10 ring formingcarbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl), which is optionally substituted with one or more (e.g., 1to 3) suitable substituents, e.g., methyl substituted cyclopropyl.

As used herein, the term “heterocyclyl” refers to a saturated orunsaturated, monovalent, monocyclic or bicyclic residue having 2, 3, 4,5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., 1, 2, 3 or 4)heteroatom-containing groups selected from the group consisting ofC(=O), O, S, S(=O), S(=O)₂, and NR^(d) wherein R^(d) represents ahydrogen atom, C₁₋₆ alkyl, or C₁₋₆ haloalkyl group, in the ring. Aheterocyclyl may be linked to the rest of a molecule through any one ofthe carbon atoms or a nitrogen atom (if present). In particular, 3- to10-membered heterocyclyl refers to a group having 3 to 10 carbon atomsand heteroatom(s) in the ring, such as, but are not limited to,oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl,dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl,pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl,thiomorpholinyl, piperazinyl or trithianyl.

As used herein, the term “aryl” refers to an all-carbon monocyclic orfused-ring polycyclic aromatic group having a conjugated π electronsystem. For example, as used herein, the term “C₆₋₁₀ aryl” refers to anaromatic group containing 6 to 10 carbon atoms, such as phenyl ornaphthyl. Aryl is optionally substituted with one or more (such as 1 to3) suitable substituents (e.g., halogen, -OH, -CN, -NO₂, C₁₋₆ alkyl).

The term “aralkyl” preferably means aryl substituted alkyl, wherein aryland alkyl are as defined herein. Normally, the aryl group may have 6-10carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplaryaralkyl group includes, but is not limited to, benzyl, phenylethyl,phenylpropyl, phenylbutyl.

As used herein, the term “heteroaryl” refers to a monovalent monocyclic,bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11,12, 13 or 14 ring atoms, particularly 1 or 2 or 3 or 4 or 5 or 6 or 9 or10 carbon atoms, and containing at least one heteroatom (such as O, N,or S), which can be same or different. Moreover, in each case, it can bebenzo-fused. In particular, heteroaryl is selected from the groupconsisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl etc., and benzo derivatives thereof; or pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzoderivatives thereof.

The “mixture of the enantiomers in all ratios” as used herein has thesame meaning as the “mixture of the enantiomers in any ratio”.

DETAILED DESCRIPTION OF THE INVENTION Example 1a: General PreparationMethod for Compounds 1-5

L-homoserine lactone hydrochloride (1a-1) (ee value of 99%, 0.1 mol) wasadded to a round bottom flask, and alcohol (the molar ratio ofhomoserine lactone hydrochloride to alcohol was about 1:(10~15)) wasadded. The temperature of the system was lowered to 10° C., and thionylchloride (0.3 mol) was slowly dropwise added. The system temperature wasmaintained at 10° C., and stirred for 30 min. The temperature wasgradually raised to 35° C., and the reaction was stirred for 20 hours,during which bubbles were continuously generated. The reaction wasmonitored by LC-MS or LC, until the reaction was complete (for completereaction of certain substrates, raising reaction temperature wasnecessary). The temperature of the system was lowered to roomtemperature, the remaining thionyl chloride and solvent were distilledoff under reduced pressure, the solid residue was slurried with 100 mLof a mixed solvent of n-hexane and ethyl acetate (the volume ratio ofn-hexane to ethyl acetate was 2:1), and the filter cake was obtainedthrough filtration. The wet product 1a-2 was neutralized with ammoniawater, the system was adjusted to pH 7-8, and extracted with ethylacetate. The organic phase was collected, dried and concentrated toobtain the target product compound 1a-3.

Example 1b: Preparation of Compound 16

Step 1

The synthesis was conducted using compound 16-1 as the starting material(the synthesis described in Weitz, Iris S. et al., Journal of OrganicChemistry (1997), 62(8), 2527-2534, can be referred to). At roomtemperature, compound 16-1 (40 mmol), DCM (20 ml), carbon tetrachloride(20 ml) and triphenylphosphine (120 mmol) were added to a round bottomflask, and then stirred at room temperature for 2 hours. TLC indicatedthat the raw materials underwent a complete reaction, and compound 16-2was obtained by column chromatography at a yield of 50%.

MS (ESI): m/z [M+H]⁺ calculated for C₁₁H₂₂ClN₂O₃: 265.13; found: 265.1.

¹H NMR (400 MHz, CDCl₃) δ 4.84 (td, J = 8.8, 4.0 Hz, 1H), 3.80 - 3.44(m, 2H), 3.12 (s, 3H), 2.97 (s, 3H), 2.16 - 2.03 (m, 1H), 1.96 (ddt, J =14.5, 8.9, 5.6 Hz, 1H), 1.43 (s, 9H).

Step 2

Compound 16-2 (20 mmol) was added to a round bottom flask, followed byaddition of 1,4-dioxane (60 ml) and 36% HCl (16 ml), and the reactionwas stirred at room temperature overnight. The reaction solution wasconcentrated, and then ammonia water was added for neutralization, withthe pH being adjusted to 7-8. The mixture was extracted with ethylacetate, dried and concentrated to obtain compound 16.

Homoserine analogues in the following table were prepared by the methodsof Example 1a, Example 1b or similar methods known in the art.

No. Homoserine analogue Brief description of the preparation methodCharacterization data 1.

The alcohol in Example 1a was replaced with methanol. MS (ESI): m/z[M+H]⁺ calculated for C₅H₁₁ClNO₂: 152.05; found: 152.1. ¹H NMR (400 MHz,CDCl₃) δ 3.74 - 3.55 (m, 6H), 2.47 (s, 2H), 2.19 - 2.09 (m, 1H), 1.96-1.82 (m, 1H). 2.

The alcohol in Example 1a was replaced with n-propanol. MS (ESI): m/z[M+H]⁺ calculated for C₇H₁₅ClNO₂: 180.08; found: 180.1. ¹H NMR (400 MHz,CDCl₃) δ 3.98 (tt, J = 7.1, 3.6 Hz, 2H), 3.69 - 3.49 (m, 3H), 2.10 (ddt,J = 14.1, 8.3, 5.6 Hz, 1H), 1.82 (ddt, J = 14.5, 9.0, 5.6 Hz, 1H), 1.73(s, 2H), 1.61 - 1.52 (m, 2H), 0.85 (t, J = 7.4 Hz, 3H). 3.

The alcohol in Example 1a was replaced with isopropanol. MS (ESI): m/z[M+H]⁺ calculated for C₇H₁₅ClNO₂: 180.08; found: 180.1. ¹H NMR (400 MHz,DMSO-d₆) δ 4.91 (td, J = 6.3, 1.6 Hz, 1H), 3.81 - 3.62 (m, 2H), 3.39(dt, J = 9.3, 3.6 Hz, 1H), 2.05 - 1.93 (m, 1H), 1.93 - 1.70 (m, 3H),1.20 (t, J = 5.7 Hz, 6H). ¹³C NMR (100 MHz, DMSO-d₆) δ 174.7, 67.5,51.5, 42.1, 37.04, 21.5. 4.

The alcohol in Example 1a was replaced with n-butanol. MS (ESI): m/z[M+H]⁺ calculated for C₈H₁₇ClNO₂: 194.10; found: 194.1. ¹H NMR (400 MHz,CDCl₃) δ 4.05 (tt, J = 6.7, 3.4 Hz, 2H), 3.72 - 3.49 (m, 3H), 2.20 -2.07 (m, 1H), 1.95 (s, 2H), 1.85 (ddt, J = 14.4, 8.9, 5.6 Hz, 1H),1.61 - 1.51 (m, 2H), 1.31 (h, J = 7.6 Hz, 2H), 0.86 (q, J = 6.9 Hz, 3H).5.

The alcohol in Example 1a was replaced with isobutanol. MS (ESI): m/z[M+H]⁺ calculated for C₈H_(J7)ClNO₂: 194.10; found: 194.1. ¹H NMR (400MHz, DMSO-d₆) δ 3.92 - 3.65 (m, 4H), 3.48 (dd, J = 9.1, 4.5 Hz, 1H),2.16 -1.73 (m, 5H), 0.90 (d, J = 6.8 Hz, 6H). ¹³C NMR (100 MHz, DMSO-d₆)δ 175.1, 70.0, 51.5, 42.1, 37.1, 27.3, 18.8. 6.

It was prepared according to a method similar to that disclosed in WO2006117552 A1. ---- 7.

It was prepared according to a method disclosed in WO 98/58256. ---- 8.

It was prepared according to a method similar to that disclosed inJournal of Organic Chemistry (2007), 72(21), 8046-8053. MS (ESI): m/z M⁺calculated for C₁₀H₂₀NO₃S⁺: 234.12; found: 234.1 ¹H NMR (400 MHz,DMSO-d₆) δ 8.36 (dd, J = 8.1, 2.8 Hz, 1H), 4.35 (dddd, J = 10.5, 7.7,4.7, 2.4 Hz, 1H), 4.10 (qd, J = 7.1, 2.1 Hz, 2H), 3.36 (ddt, J = 11.9,5.8, 2.9 Hz, 2H), 2.95 (dd, J = 4.5, 2.6 Hz, 6H), 2.28 - 2.11 (m, 1H),2.11 - 1.95 (m, 1H), 1.87 (d, J = 1.3 Hz, 3H), 1.18 (td, J = 7.1, 2.1Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 170.7, 169.7, 61.0, 50.6, 25.2,24.4, 22.5, 14.0. 9.

It was prepared according to a method similar to that disclosed in CN110386882 A. MS (ESI): m/z [M+H]⁺ calculated for C₁₃H₁₇ClNO₃: 270.09;found: 270.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (d, J = 7.6 Hz, 1H),8.01 - 7.76 (m, 2H), 7.60 - 7.53 (m, 1H), 7.49 (t, J = 7.3 Hz, 2H), 4.61(ddd, J = 9.6, 7.6, 5.0 Hz, 1H), 4.13 (qd, J = 7.1, 1.8 Hz, 2H), 3.89 -3.62 (m, 2H), 2.36 - 2.13 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). ¹³C NMR(100 MHz, DMSO-d₆) δ 171.5, 166.8, 133.6, 131.6, 128.3, 127.5, 60.8,50.3, 41.9, 33.3, 14.1. 10.

It was prepared according to a method similar to that disclosed in CN110386882 A. MS (ESI): m/z [M+H]⁺ calculated for C₁₃H₁₉ClNO₄S: 320.07;found: 320.1. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (d, J = 9.0 Hz, 1H), 7.64(dd, J = 8.2, 1.6 Hz, 2H), 7.44 - 7.30 (m, 2H), 3.95 (tdd, J = 8.9, 6.3,2.2 Hz, 1H), 3.85 (q, J = 7.1 Hz, 2H), 3.59 (dt, J = 11.3, 5.7 Hz, 1H),3.51 (ddd, J = 11.0, 8.1, 5.7 Hz, 1H), 2.43 - 2.25 (m, 3H), 1.97 (ttd, J= 14.3, 10.4, 9.2, 7.4 Hz, 2H), 1.02 (t, J = 7.1 Hz, 3H). ¹³C NMR (101MHz, DMSO-d₆) δ 170.6, 142.7, 138.1, 129.4, 126.5, 60.9, 53.0, 41.0,34.8, 20.9, 13.7. 11.

It was prepared according to a method disclosed in WO 2020/145514 A1. MS(ESI): m/z [M+H]⁺ calculated for C₈H₁₅ClNO₃: 208.08; found: 208.1. ¹HNMR (400 MHz, DMSO-d₆) δ 8.31 (d, J = 7.7 Hz, 1H), 4.37 (ddd, J = 9.4,7.6, 4.9 Hz, 1H), 4.09 (qd, J = 7.1, 1.8 Hz, 2H), 3.83 - 3.44 (m, 2H),2.08 (dddd, J = 20.1, 14.4, 8.2, 4.2 Hz, 2H), 1.86 (s, 3H), 1.18 (t, J =7.1 Hz, 3H). ¹³C NMR (100 MHz, DMSO-d₆) δ 171.6, 169.6, 60.7, 49.6,41.5, 33.7, 22.3, 14.0. 12.

It was prepared according to a method disclosed in CN 110386882 A MS(ESI): m/z [M+H]⁺ calculated for C₉H₁₇ClNO₄: 238.09; found: 238.1. ¹HNMR (400 MHz, DMSO-d₆) δ 7.60 (d, J = 8.0 Hz, 1H), 4.14 (dddt, J = 27.3,9.5, 7.1, 3.7 Hz, 3H), 4.00 (q, J = 7.1 Hz, 2H), 3.82 - 3.46 (m, 2H),2.08 (ddt, J = 13.1, 8.9, 4.7 Hz, 2H), 1.18 (q, J = 6.9 Hz, 6H). 13.

It was prepared according to a method reported in J. Med. Chem. 1994,37, 2950-2957. MS (ESI): m/z [M+H]⁺ calculated for C₁₁H₂₁ClNO₄: 266.12;found: 266.2. ¹H NMR (400 MHz, DMSO-d₆) δ 7.33 (d, J = 8.0 Hz, 1H),4.53 - 3.93 (m, 3H), 3.65 (tdd, J = 14.7, 11.0, 6.2 Hz, 2H), 2.36 - 1.90(m, 2H), 1.38 (s, 9H), 1.18 (td, J = 7.1, 3.1 Hz, 3H). ¹³C NMR (100 MHz,DMSO-d₆) δ 172.0, 155.6, 78.4, 60.6, 51.1, 41.7, 33.4, 28.1, 14.0. 14.

Compound 16-1 in Example 1b was replaced with MS (ESI): m/z [M+H]⁺calculated for C₇H₁₆ClN₂O: 179.10; found: 179.1. ¹H NMR (400 MHz, D₂O) δ4.06 (t, J = 6.9 Hz, 1H), 3.93 (p, J = 6.6 Hz, 1H), 3.78 - 3.54 (m, 2H),2.31 (qd, J = 6.7, 2.0 Hz, 2H), 1.13 (dd, J = 6.6, 2.4 Hz, 6H). ¹³C NMR(100 MHz, D₂O) δ 167.5, 51.3, 42.3, 39.7, 33.4, 21.2, 21.1. 15.

Compound 16-1 in Example 1b was replaced with MS (ESI): m/z [M+H]⁺calculated for C₈H₁₈ClN₂O: 193.11; found: 193.1. ¹H NMR (400 MHz, D₂O) δ4.18 (t, J = 6.9 Hz, 1H), 3.79 - 3.65 (m, 2H), 3.33 (dt, J = 13.8, 7.0Hz, 1H), 3.22 (dt, J = 13.6, 6.9 Hz, 1H), 2.42 - 2.31 (m, 2H), 1.59 -1.49 (m, 2H), 1.41 - 1.26 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). ¹³C NMR(100 MHz, D₂O) δ 168.5, 51.4, 39.8, 39.5, 33.5, 30.2, 19.4, 13.0. 16.

See Example 1b MS (ESI): m/z [M+H]⁺ calculated for C₆H₁₄ClN₂O: 165.08;found: 165.1. ¹H NMR (400 MHz, D₂O) δ 4.65 (dd, J = 7.7, 4.8 Hz, 1H),3.79 - 3.64 (m, 2H), 3.09 (s, 3H), 2.93 (s, 3H), 2.30 (dddd, J = 13.7,11.2, 7.7, 3.9 Hz, 2H). ¹³C NMR (100 MHz, D₂O) δ 168.5, 48.6, 39.8,37.1, 35.9, 32.6. 17.

It was prepared according to a method similar to that disclosed inJournal of Organic Chemistry (1986), 51(26), 5047-50. MS (ESI): m/z[M+H]⁺ calculated for C₁₅H₂₂NO₆S: 344.40; found: 344.4. ¹H NMR (400 MHz,CDCl₃) δ 7.93 - 7.49 (m, 2H), 7.36 - 7.17 (m, 2H), 5.85 (d, J = 9.1 Hz,1H), 4.24 - 4.06 (m, 2H), 4.06 - 3.92 (m, 3H), 2.41 (s, 3H), 2.14 - 2.03(m, 1H), 2.00 (s, 4H), 1.11 (t, J= 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃)δ 171.1, 170.6, 143.5, 136.6, 129.5, 127.1, 61.7, 59.8, 52.8, 31.8,21.3, 20.6, 13.7.

Example 2

At -10° C., n-propanol (0.9 mol), triethylamine (0.9 mol) and n-hexane(450 ml) were added to a round bottom flask, anddichloro(methyl)phosphane (0.45 mol) was added dropwise through aconstant-pressure dropping funnel for about 1 hour. The reaction waswarmed to 0° C., and allowed to proceed for 2 hours for completereaction. The mixture was filtered, the solid was washed with n-hexane(150 ml × 2), and the mother liquor was evaporated under reducedpressure to remove the solvent. Dipropyl methylphosphonite (colorlessliquid, yield: 86%, content: 94%) was obtained through fractionation(the fractionation temperature is not higher than 60° C.).

MS (ESI): m/z [M+H]⁺ calculated for C₇H₁₈O₂P: 165.11; found: 165.1.

¹H NMR (400 MHz, CDCl₃) δ 3.65 (ddddt, J = 10.0, 6.2, 5.0, 3.5, 1.7 Hz,4H), 1.51 (q, J = 7.1 Hz, 4H), 1.12 (dd, J = 8.3, 1.2 Hz, 3H), 0.82 (td,J = 7.4, 1.1 Hz, 6H).

¹³C NMR (100 MHz, CDCl₃) δ 68.2, 24.6, 19.9, 10.2.

³¹P NMR (160 MHz, CDCl₃) δ 33.5.

The following compounds were prepared according to a method similar tothat described above.

No. Alkyl phosphonite Difference as compared with the method in Example2 Characterization data 1

n-propanol was replaced with isopropanol. MS (ESI): m/z [M+H]⁺calculated for C₇H₁₈O₂P: 165.11; found: 165.1. ¹H NMR (400 MHz, CDCl₃) δ4.11 (dp, J = 9.6, 6.2 Hz, 2H), 1.18 - 1.06 (m, 15H). ¹³C NMR (100 MHz,CDCl₃) δ 70.3, 24.7, 21.5. ³¹P NMR (160 MHz, CDCl₃) δ 30.1. 2

n-propanol was replaced with n-butanol. MS (ESI): m/z [M+H]⁺ calculatedfor C₉H₂₂O₂P: 193.14; found: 193.1. ¹H NMR (400 MHz, CDCl₃) δ 3.70 (pd,J = 7.5, 7.1, 3.3 Hz, 4H), 1.53 -1.43 (m, 4H), 1.35 - 1.22 (m, 4H),1.15 - 1.07 (m, 3H), 0.83 (qd, J = 7.3, 6.8, 3.3 Hz, 6H). ¹³C NMR (100MHz, CDCl₃) δ 66.3, 33.5, 20.0, 19.0, 13.7. ³¹P NMR (160 MHz, CDCl₃) δ28.7.

Example 3

Under a nitrogen atmosphere, at -10° C., a solution of a compound ofFormula (IV) (0.6 eq, 90% purity) in chlorobenzene was added to a roundbottom flask, and a solution of dichloro(methyl)phosphane (0.6 eq, 98%purity) in chlorobenzene was added dropwise through a constant-pressuredropping funnel at a rate of 1 d/s. After the dropwise addition wascomplete, the reaction was stirred for 10 min (at this time, thecorresponding compound of Formula (III)

could be generated, wherein Hal² is chlorine, and R₂ is either R₃ orR₄). Subsequently, a solution of a compound of Formula (IIa) (1.0 eq)and triethylamine (1.2 eq, 98% purity) in chlorobenzene was addedthereto at a rate of 4 d/s, and the stirring was continued for 30 minafter the dropwise addition. The reaction was warmed to room temperatureand stirred for 1h, and then the temperature was raised to 90° C., andthe reaction was continued for 12h. The reaction was naturally cooled toroom temperature, filtered with suction, and the filter cake was washedwith chlorobenzene (150 mL x 3). The filtrate was rotary evaporated toremove chlorobenzene, resulting in an intermediate. The intermediate wasadded with 100 mL concentrated hydrochloric acid (36%), heated to 90°C., and the reaction was allowed to proceed for 10h. MS detectionindicated that the intermediate disappeared, the mixture was naturallycooled to room temperature, rotary evaporated to remove the solvent, andadded with 95% ethanol (300 mL). The solution was heated to reflux untilthe crude product was completely dissolved, naturally cooled forcrystallization, filtered and dried to obtain L-glufosinatehydrochloride.

According to the above method, L-glufosinate hydrochloride was preparedfrom the substrates in the table below. The reaction yield and ee valueof the product are shown in the table below.

No. Compound of Formula (IIa) Compound of Formula (IV) Yield ee value 1.

76% 98% 2.

78.2% 98% 3.

65.1% 95% 4.

79.7% 98% 5.

48.4% 99% 6.

24.8% 65% 7.

38% 86% 8.

70.80% 96% 9.

34.1% 93% 10.

35% 97% 11.

19.4% 53% 12.

22% 91% 13.

43% 73% 14.

82% 97% 15.

74.5% 95%

Example 4

Under a nitrogen atmosphere, at -10° C., a solution of diethylmethylphosphonite (861.7 g, 0.55 eq, 90% purity) in chlorobenzene (6.0kg) was added to a 20 L Jacketed Glass Reactor, and a solution ofdichloro(methyl)phosphane (679.5 g, 0.55 eq, 98% purity) inchlorobenzene (2.0 kg) was added dropwise through a constant-pressuredropping funnel at a rate of 5 d/s. After the dropwise addition wascomplete, the reaction was stirred for 10 min (at this time,chloro(ethoxy)(methyl)phosphane

could be generated). Subsequently, a solution of the compound of Formula(IIa)-butly ester (2.0 kg, 1.0 eq) and triethylamine (1.2 kg, 1.1 eq,98% purity) in chlorobenzene (8.0 kg) was added thereto at a rate of 10d/s, and the stirring was continued for 30 min after the dropwiseaddition. The reaction was warmed to room temperature and stirred for 30min, and then the temperature was raised to 90° C., and the reaction wascontinued for 2 h. The reaction was naturally cooled to roomtemperature, filtered with suction, and the filter cake was washed withchlorobenzene (2.5 L x 2). The filtrate was rotary evaporated to removechlorobenzene, resulting in an intermediate. The intermediate was addedwith 4.2 kg 36% wt. hydrochloric acid, heated to 95° C., and thereaction was allowed to proceed for 10 h, and at thesame time, butanolgenerated was distilled off. MS detection indicated that theintermediate disappeared, the mixture was naturally cooled to roomtemperature, rotary evaporated to remove the solvent, and added with 95%ethanol (6 L). The solution was heated to reflux until the crude productwas completely dissolved, naturally cooled for crystallization, filteredand dried to obtain L-glufosinate hydrochloride (white, yield 88%, eevalue 98%).

In addition to those described herein, according to the foregoingdescription, various modifications to the present invention would beapparent to those skilled in the art. Such modifications are intended tofall within the scope of the appended claims. Each reference citedherein (including all patents, patent applications, journal articles,books and any other disclosures) are incorporated herein by reference inits entirety.

What is claimed is: 1-31. (canceled)
 32. A method for preparingglufosinate of formula (I) or a salt, an enantiomer thereof or a mixtureof the enantiomers in all ratios, characterized in that the methodcomprises the following steps:

a) reacting a compound of formula (II) or a salt, an enantiomer thereofor a mixture of the enantiomers in all ratios,

with one or more compounds of formula (III) or a mixture; the mixturebeing a mixture comprising one or more compounds of formula (IV) and oneor more compounds of formula (V); or a mixture comprising one or morecompounds of formula (IV) and one or more compounds of formula (III); ora mixture comprising one or more compounds of formula (V) and one ormore compounds of formula (III); or a mixture comprising one or morecompounds of formula (III), one or more compounds of formula (IV) andone or more compounds of formula (V);

b) reacting the intermediate, no matter whether it is isolated or not,in the presence of water and an acid or a base to obtain the glufosinate(I) or a salt, an enantiomer thereof or a mixture of the enantiomers inall ratios; wherein when PG is an amino protecting group, a step ofremoving the amino protecting group can be further comprised; wherein:LG is Hal¹, -OTs or

Hal¹ and Hal² are each independently halogen, e.g., fluorine, chlorine,bromine or iodine; PG is hydrogen or an amino protecting group, and theamino protecting group preferably is -C(=O)R, -C(=O)OR or -S(=O)₂R; A is-NHR₁, -NR₁R₁, or -OR₁; R, R₁, R_(1′), R₂, R₃ and R₄ are eachindependently selected from the group consisting of C₁-C₆ alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, C₆₋₁₂ aralkyl, 5- to 14-membered heteroaryl and3- to 10-membered heterocyclyl, and when the mixture comprises themixture of one or more compounds of formula (IV) and one or morecompounds of formula (III), or when the mixture comprises the mixture ofone or more compounds of formula (III), one or more compounds of formula(IV) and one or more compounds of formula (V), R₂ is either R₃ or R₄;and the chiral carbon atom is labeled with *; and provided that at leastone of the following conditions is met: 1) the compound of formula (II)is not

2) the compound of formula (III) is not

3) the compound of formula (IV) is not

4) the compound of formula (V) is not

.
 33. The method according to claim 32, wherein the glufosinate offormula (I) or a salt thereof prepared by the method is enantiomericallypure,

characterized in that the compound of the formula (II) in the step a) isenantiomerically pure.
 34. The method according to claim 32,characterized in that the enantiomeric ratio is (L): (D)-enantiomer or(D):(L)-enantiomer of 50.5:49.5 to 99.5:0.5.
 35. The method according toclaim 32, characterized in that R is C₁-C₆ alkyl or C₆₋₁₀ aryl,preferably is methyl, ethyl, tert-butyl, phenyl or p-methylphenyl;preferably, the PG is hydrogen, -C(=O)CH₃, -C(=O)Ph, -C(=O)OC₂H₅,-C(=O)OC(CH₃)₃ or

.
 36. The method according to claim 32, characterized in that the Hal¹is chlorine, bromine or iodine; preferably, LG is chlorine, bromine,iodine, -OTs or

more preferably, LG is chlorine, bromine or iodine; or the Hal² ischlorine.
 37. The method according to claim 32, characterized in thatthe R₁, R_(1′), R₂, R₃ and R₄ are each independently C₁-C₆ alkyl orC₆₋₁₂ aralkyl, preferably are C₁-C₄ alkyl or benzyl.
 38. The methodaccording to claim 32, characterized in that the R₁ and R_(1′) are eachindependently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl orbenzyl; preferably, A is -NHCH₂CH₂CH₂CH₃, -N(CH₃)₂, -OCH₃, -OCH₂CH₃,-OCH₂CH₂CH₃, -OCH(CH₃)₂, OCH₂CH₂CH₂CH₃, -OCH₂CH(CH₃)₂ or -OBn.
 39. Themethod according to claim 32, characterized in that the R₂ is methyl,ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably is n-propyl,isopropyl or n-butyl; or R₃ is methyl, ethyl, n-propyl, isopropyl,n-butyl or isobutyl, preferably is n-propyl, isopropyl or n-butyl; or R₄is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferablyis n-propyl, isopropyl or n-butyl.
 40. The method according to claim 32,characterized in that the mixture is a mixture of one or more compoundsof formula (IV) and one or more compounds of formula (III), and themolar ratio of the compounds of formula (IV) to the compounds of formula(III) is (0.9-1.1): 1 or (0.05-1.1): 1; or the mixture is a mixture ofone or more compounds of formula (V) and one or more compounds offormula (III), and the molar ratio of the compounds of formula (V) tothe compounds of formula (III) is (0.9-1.1): 1 or (0.05-1.1): 1; or themixture is a mixture comprising one or more compounds of formula (IV)and one or more compounds of formula (V), and the molar ratio of thecompounds of formula (IV) to the compounds of formula (V) is(0.9-1.1):1.
 41. The method according to claim 32, characterized in thatin the step a), the reaction temperature is 20 to 200° C., preferably 90to 140° C.
 42. The method according to claim 32, characterized in thatthe step a) is carried out in the presence of a base.
 43. The methodaccording to claim 42, characterized in that the base in the step a) isan organic base selected from the group consisting of an organic amine,pyridine or a pyridine derivative having 1-3 substituents attached toone or more carbon atoms in the heterocycle, piperidine or a piperidinederivative having 1-3 substituents attached to one or more carbon atomsin the heterocycle or ammonia.
 44. The method according to claim 43,characterized in that the organic base is selected from the groupconsisting of triethylamine, piperidine or pyridine.
 45. The methodaccording to claim 32, characterized in that in the step a), the molarratio of the base to the total amounts of the compound of formula (III)and the compound of formula (V) is (1-10):1.
 46. The method according toclaim 32, characterized in that in the step a), the reaction is carriedout under a solvent-free condition or in an inert solvent.
 47. Themethod according to claim 32, characterized in that in the step a), theinert solvent is selected from any one or more of benzene solvents,amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents,sulfone or sulfoxide solvents, ether solvents or ester solvents;preferably, the inert solvent is selected from any one or more ofbenzene solvents, amide solvents, halogenated hydrocarbon solvents,ether solvents or ester solvents.
 48. The method according to claim 46,characterized in that in the step a), the inert solvent is selected fromany one or more of chlorobenzene, trimethylbenzene, 1,4-dioxane,1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone,N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran,methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butylacetate.
 49. The method according to claim 32, characterized in that inthe step a), the molar ratio of the compound of formula (III) or themixture to the compound of formula (II) is 1:(0.8-10), preferably1:(1-3); or the molar ratio of the compound of formula (II) to thecompound of formula (III) or the mixture is 1:(0.8-10), preferably1:(1-3).
 50. The method according to claim 32, characterized in that inthe step b), an inorganic acid or an organic acid is added.
 51. Themethod according to claim 50, characterized in that the inorganic acidis hydrochloric acid or sulfuric acid.
 52. The method according to claim32, characterized in that in the step b), the base is an inorganic baseselected from the group consisting of alkali metal hydroxide,alkali-earth metal hydroxide, alkali metal carbonate, alkali-earth metalcarbonate, alkali metal bicarbonate or alkali-earth metal bicarbonate oran organic base.
 53. The method according to claim 52, characterized inthat the base is NaOH, KOH or Ba(OH)₂.
 54. The method according to claim32, characterized in that in the step b), the reaction temperature is 20to 150° C.
 55. The method according to claim 32, characterized in thatthe compound of formula (II) is selected from the group consisting of:No. The compound of formula (II)
 1.


2.


3.


4.


5.


6.


7.


8.


9.


10.


11.


12.


13.


14.

and/or, the compound of formula (IV) is

compound of formula (V) is

.
 56. A compound of formula (II) or a salt thereof,

wherein the compound of formula (II) is selected from the groupconsisting of:

.
 57. A method for preparing glufosinate or a salt thereof, orL-glufosinate or a salt thereof, wherein the method comprises a step ofusing the compound according to claim 56.